Cardiovascular calcification is a disease of dysregulated mineral metabolism, which leads to increased risk of cardiovascular events and potentially death. Microcalcifications located in the thin fibrous cap overlying the necrotic core of atherosclerotic plaques may cause microfractures, which can lead to acute thrombosis and even sudden death due to fatal myocardial infarction (Huang H, Circulation, 2001; Virmani R, 2006; Vengrenyuk Y, 2006). Various therapeutic agents have been investigated to target cardiovascular calcification; these include statins (Aikawa E, Circulation, 2007; Monzack et al, 2009; Osman L, Circulation, 2006; Rajamannan N M, Circulation, 2005) and mineralocorticoid receptor antagonists (Gkizas S, Cardiovasc Pharma, 2010; Jaffe I Z, ATVB, 2007), however as yet they have not proved beneficial in the clinical setting (Gilmanov D, Inter. Cardiovasc Thor Surg. 2010). Calcification in the aortic valve causes aortic stenosis and heart failure. However, the only option to treat aortic valve calcification or stenosis is surgical valve replacement, for which many patients with advanced calcification and/or impaired cardiac function have no indication.
Physiological mineralization is initiated in bone and cartilage in association with matrix vesicles released by osteoblasts and chondrocytes (Anderson H C 2003). Due to this it is suggested that they also play a sizeable role in pathological ectopic calcification (Shao J S, Cai J and Towler D A 2006). In medial calcification in patients with chronic kidney disease, vascular smooth muscle cells have already been identified to release calcifying matrix vesicles (30-300 nm) that serve as a nidus for mineral nucleation (Kapustin et al 2011; Reynolds et al 2009). Whilst this is a feasible notion for medial calcification, in intimal calcification where macrophages are in abundance and smooth muscle cells are lacking, macrophages may play a greater role in the calcification process.
Arterial microcalcifications in the thin cap overlying the necrotic core in the intima of atherosclerotic plaques may cause compliance mismatch, increase local stress, and promote microfractures—leading to plaque rupture causing acute cardiovascular events (Libby P. & Aikawa M., Nat Med, 2002, 8:1257-62 and Li et al., Am J Physiol Cell Physiol., 2012, 302:C658-C665). Atherosclerotic plaques containing “spotty” calcifications consisting of calcified vesicles (precursors to microcalcification) have increased stress, thus making them more susceptible to rupture (Wenk et al., J Biomech Eng., 2010, 132:091011).
Patients with chronic renal disease (CRD) have heightened susceptibility to atherosclerosis, a greater risk of intimal and medial calcification, as well as aortic valve stenosis, and a high cardiovascular mortality (Aikawa et al., Circulation, 2009, 119:1785-94 and Goodman et al., Am J Kidney Dis., 2004, 43:572-9). The added complication of hyperphosphatemia, may trigger release of matrix vesicles (MV) also termed as extracellular vesicles (Chen et al., J Bone Miner Res., 2008, 23:1798-805 and Kapustin et al., Circ Res., 2011, 109:e1-12). Cells release MV to initiate mineralization in both non-pathological (Anderson H. C., Curr Rheumatol Rep., 2003, 5:222-6) and pathological conditions (Chen et al., J Bone Miner Res., 2008, 23:1798-805; Kapustin et al., Circ Res., 2011, 109:e1-12; Anderson H. C., Curr Rheumatol Rep., 2003, 5:222-6; and Kim K. M., Fed Proc., 1976, 35:156-62)
Smooth muscle cell (SMC)-derived MV contribute to medial calcification in CRD patients (Kapustin et al., Circ Res., 2011, 109:e1-12) and interstitial valvular cell-derived MV may contribute to aortic valve calcification. Inventors' previous molecular imaging studies co-localized early stages of atherosclerotic intimal calcification/microcalcification with macrophages (Aikawa et al., Circulation, 2007, 116:2841-50). While arterial and valvular calcification promotes heart attacks and aortic valve stenosis, which represent major health problems and economic burden in the United States, no medical therapies are available for calcification.
Therefore, there exists a need for an effective method of inhibiting and preventing cardiovascular calcification, such as arterial and valvular microcalcification.